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Osimertinib in Treating Patients With Stage IIIB-IV or Recurrent Non-small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations

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ClinicalTrials.gov Identifier: NCT03191149
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well osimertinib works in treating patients with non-small cell lung cancer with EGFR exon 20 insertion mutation that is stage IIIB-IV or has come back. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
EGFR Exon 20 Insertion Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Stage IV Non-Small Cell Lung Cancer AJCC v7 Other: Laboratory Biomarker Analysis Drug: Osimertinib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the best objective response rate of AZD9291 (osimertinib) among patients with EGFR exon 20 insertions.

SECONDARY OBJECTIVES:

I. To determine the safety profile of 160 mg once daily (QD) dose of AZD9291 (osimertinib) in patients with EGFR Exon 20 insertion mutations.

II. To determine the progression-free survival. III. To determine the overall survival.

TERTIARY OBJECTIVES:

I. To characterize molecular markers of response to treatment in circulating tumor deoxyribonucleic acid (DNA).

II. To evaluate biomarkers of response to treatment through retrospective analyses of pre-treatment tumor tissue.

III. To identify resistance mechanisms to AZD9291 (osimertinib) through post-progression tumor biopsies and circulating tumor (ct)DNA.

OUTLINE:

Patients receive osimertinib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and every 3 months for up to 5 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of AZD9291 (Osimertinib) in Advanced NSCLC Patients With Exon 20 Insertion Mutations in EGFR
Actual Study Start Date : April 5, 2018
Estimated Primary Completion Date : July 31, 2022
Estimated Study Completion Date : July 31, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Treatment (osimertinib)
Patients receive osimertinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Osimertinib
Given PO
Other Names:
  • AZD-9291
  • AZD9291
  • Mereletinib
  • Tagrisso




Primary Outcome Measures :
  1. Best objective response evaluated via Response Evaluation Criteria in Solid Tumors 1.1 criteria [ Time Frame: Up to 5 years ]
    Categorical data, such as response rates (complete response + partial response), will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Any continuous outcomes will be analyzed using Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for multiple associations with outcome. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From registration to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios. Comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.

  2. Overall survival (OS) [ Time Frame: From registration to death from any cause, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate hazard ratios. Comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.

  3. Incidence of adverse events determined using Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
    Categorical data, such as toxicity, will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Any continuous outcomes will be analyzed using Wilcoxon rank sum test, and multivariable linear regression models may be used to adjust for multiple associations with outcome. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. The method of Atkinson and Brown will be used for the estimation of the confidence interval for response.


Other Outcome Measures:
  1. Characterization of molecular markers of response to treatment in circulating tumor deoxyribonucleic acid (ctDNA) [ Time Frame: Baseline up to 5 years ]
    Initial analyses of data will utilize tests for association comparing the frequency of a particular genomic aberration at baseline and at progression (for example, using McNemar's test) and association between alterations and baseline characteristics (for example, using Fisher's exact test). More sophisticated analyses may include multivariable logistic regression modeling and/or competing risks analysis, however it is expected that analyzable results will not be obtained from 100% of patients (either due to things like assay failure, inability to biopsy at progression due to poor patient health, etc).

  2. Biomarkers of response to treatment through retrospective analyses of pre-treatment tumor tissue [ Time Frame: Baseline up to 5 years ]
    The rate of change in allelic fraction at a particular time point may be compared to baseline measures of ctDNA and that measure will be analyzed for association with patient demographics and/or disease characteristics using the Kruskal Wallis test. Landmark analyses of PFS and OS in which the landmark time is defined by the ctDNA measurements at a particular time point, may be used as well.

  3. Identification of resistance mechanisms to osimertinib through post-progression tumor biopsies and ctDNA [ Time Frame: Up to 5 years ]
    Presence or absence of mutations in plasma will be analyzed for association with other variables using Fisher's exact test. To account for the repeated measures of plasma over time, we may potentially use these data as time varying covariates in multivariable Cox models to study their impact on outcomes like PFS and OS.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must have a pathologically-confirmed diagnosis of non-small cell lung cancer (NSCLC)
  • Participants must have advanced disease - either stage IV disease, stage IIIB disease not amenable to definitive multi-modality therapy, or recurrent disease after a prior diagnosis of stage I-III disease; all staging is via the American Joint Committee on Cancer (AJCC)/International Association for the Study of Lung Cancer (IASLC) 7th edition staging criteria
  • An EGFR exon 20 insertion mutation must be detected in the tumor tissue; patients may be enrolled in the study based on an exon 20 insertion EGFR mutation detected by any Clinical Laboratory Improvement Act (CLIA)-certified tissue assay

    • NOTE: Testing results are to be submitted via Medidata Rave and the study chair or delegate will review the reports
  • Patients must have measurable disease; baseline measurements and ALL sites of disease must be obtained within 4 weeks to registration
  • Patients must have previously received at least one line of therapy for their advanced lung cancer; there are no restrictions on the maximum number of prior therapies allowed
  • Participants may not have received any prior treatment with therapies targeting PDL1, PD1 or CTLA4
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Hemoglobin >= 9.0 g/L within 4 weeks before randomization
  • Leukocytes >= 3,000/mcL within 4 weeks before randomization
  • Absolute neutrophil count >= 1,500/mcL within 4 weeks before randomization
  • Platelets >= 100,000/mcL within 4 weeks before randomization
  • Total bilirubin < 1.5 x upper limit of normal (ULN) if no liver metastases or =< 3 times ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinaemia) or liver metastases within 4 weeks before randomization
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal; for patients with known hepatic metastases AST and/or ALT =< 5 x ULN within 4 weeks before randomization
  • Creatinine =< 1.5 x institutional upper limit of normal within 4 weeks before randomization
  • Participants may not have clinically active or symptomatic interstitial lung disease or interstitial pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention), or a history of clinically significant interstitial lung disease or radiation pneumonitis
  • Participants may not have had radiation to the lung fields within four weeks (28 days) of starting treatment; for patients receiving palliative radiation to thoracic vertebrae, ribs or other sites where the radiation field includes the lungs, radiation must be completed at least two weeks before starting treatment; for all palliative radiation to all other sites, at least 7 days must have elapsed prior to starting to treatment; at least six months (180 days) must have elapsed from radiation given with curative intent
  • Participants may not have clinically symptomatic brain metastases or leptomeningeal disease; patients may be on a stable dose of corticosteroids to control brain metastases if they have been on a stable dose for two weeks (14 days) prior to study treatment and are clinically asymptomatic
  • Patients must have an echocardiogram (ECHO) or a nuclear study (multi-gated acquisition scan [MUGA] or first pass) within 4 weeks (28 days) prior to registration to treatment and must not have a left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN); if the LLN is not defined at a site, the LVEF must be > 50% for the patient to be eligible
  • Participants may not have any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs) using the screening clinic ECG machine-derived QTc value
    • No history of QT prolongation associated with other medications that required discontinuation of that medication
    • Patient must not be receiving any concomitant medications that are known to be associated with Torsades de Pointes
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval
    • Symptomatic heart failure - New York Heart Association (NYHA) grade II-IV
  • Participants may not have a second, clinically active, cancer; patients with second cancers which have been treated with curative intent and/or are currently inactive are allowed
  • Participants may not be receiving any other investigational agents; patients previously treated with investigational agents must complete a washout period of at least two weeks or five half-lives, whichever is longer, before starting treatment
  • Participants may not have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • No history of hypersensitivity active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib
  • Patients must not currently be receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 week prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
  • If medically feasible, patients taking regular medication, with the exception of potent inducers of CYP3A4, should be maintained on it throughout the study period; patients taking concomitant medications whose disposition is dependent upon breast cancer resistance protein (BCRP) and which have a narrow therapeutic index should be closely monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving osimertinib NOTE: Use of St John's wort is a contra-indication for osimertinib use
  • It is recommended that the starting and maintenance dose of rosuvastatin (due to BCRP inhibition by osimertinib) should be as low as possible and should be guided by the statin label; monitoring of low-density lipoprotein (LDL) cholesterol levels is advised; if the subject experiences any potentially relevant adverse events suggestive of muscle toxicity including unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, the statin should be stopped, creatine kinase (CK) levels should be checked, and any appropriate further management should be taken
  • Subjects taking warfarin should be monitored regularly for changes in prothrombin time or international normalized ratio (INR)
  • No unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment, with the exception of alopecia and grade 2, prior platinum-therapy-related neuropathy
  • Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Women of childbearing potential (WOCBP) and sexually active males must use an accepted and effective method of contraception while receiving protocol treatment or abstain from sexual intercourse for the duration of their participation in the study; WOCBP must use birth control for two weeks prior to the start of the treatment and continue for 6 weeks after the last dose of the study drug; sexually active male patients must use effective contraception from day 1 of treatment and continue for 4 months after the last dose of the study drug
  • Other anticancer agents and investigational agents should not be given while the subject is on study treatment
  • Supportive care and other medications that are considered necessary for the subject's wellbeing may be given at the discretion of the investigator
  • A guidance regarding potential interactions with concomitant medications is provided

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03191149


  Show 258 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Zofia Piotrowska ECOG-ACRIN Cancer Research Group

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03191149     History of Changes
Other Study ID Numbers: NCI-2017-01017
NCI-2017-01017 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA5162 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA5162 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: October 25, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action